tbuckley/cabot-search huggingface dataset:
Metacognitive therapy home-based self-help for anxiety and depression in cardiovascular disease patients in the UK: A single-blind randomised controlled trial
Authors: Adrian Wells, David Reeves, Calvin Heal, Peter Fisher, Patrick Doherty, Linda Davies, Anthony Heagerty, Lora Capobianco
Journal: PLoS Medicine (2023)

Background Anxiety and depression in cardiac rehabilitation (CR) are associated with greater morbidity, mortality, and increased healthcare costs. Current psychological interventions within CR have small effects based on low-quality studies of clinic-based interventions with limited access to home-based psychological support. We tested the effectiveness of adding self-help metacognitive therapy (Home-MCT) to CR in reducing anxiety and depression in a randomised controlled trial (RCT). Methods and findings We ran a single-blind, multi-centre, two-arm RCT. A total of 240 CR patients were recruited from 5 NHS-Trusts across North West England between April 20, 2017 and April 6, 2020. Patients were randomly allocated to Home-MCT+CR ( n = 118, 49.2%) or usual CR alone ( n = 122, 50.8%). Randomisation was 1:1 via randomised blocks within hospital site, balancing arms on sex and baseline Hospital Anxiety and Depression Scale (HADS) scores. The primary outcome was the HADS total score at posttreatment (4-month follow-up). Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Analysis was by intention to treat. The 4-month outcome favoured the MCT intervention group demonstrating significantly lower end of treatment scores (HADS total: adjusted mean difference = −2.64 [−4.49 to −0.78], p = 0.005, standardised mean difference (SMD) = 0.38). Sensitivity analysis using multiple imputation (MI) of missing values supported these findings. Most secondary outcomes also favoured Home-MCT+CR, especially in reduction of post-traumatic stress symptoms (SMD = 0.51). There were 23 participants (19%) lost to follow-up in Home-MCT+CR and 4 participants (3%) lost to follow-up in CR alone. No serious adverse events were reported. The main limitation is the absence of longer term (e.g., 12-month) follow-up data. Conclusion Self-help home-based MCT was effective in reducing total anxiety/depression in patients undergoing CR. Improvement occurred across most psychological measures. Home-MCT was a promising addition to cardiac rehabilitation and may offer improved access to effective psychological treatment in cardiovascular disease (CVD) patients. Trial registration NCT03999359 .
Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma
Authors: Vivian Changying Jiang, Yang Liu, Junwei Lian, Shengjian Huang, Alexa Jordan, Qingsong Cai, Ruitao Lin, Fangfang Yan, Joseph McIntosh, Yijing Li, Yuxuan Che, Zhihong Chen, Jovanny Vargas, Maria Badillo, John Nelson Bigcal, Heng-Huan Lee, Wei Wang, Yixin Yao, Lei Nie, Christopher R. Flowers, Michael Wang
Journal: Journal of Clinical Investigation (2023)

Bruton's tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11-knockout cells showed antitumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK/CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K/AKT/mTOR, and integrin signaling. Importantly, cotargeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.
Asparagine protects pericentral hepatocytes during acute liver injury
Authors: Yu Sun, Hadrien Demagny, Adrien Faure, Francesca Pontanari, Antoine Jalil, Nadia Bresciani, Ece Yildiz, Melanie Korbelius, Alessia Perino, Kristina Schoonjans
Journal: Journal of Clinical Investigation (2023)

The nonessential amino acid asparagine can only be synthesized de novo by the enzymatic activity of asparagine synthetase (ASNS). While ASNS and asparagine have been implicated in the response to numerous metabolic stressors in cultured cells, the in vivo relevance of this enzyme in stress-related pathways remains unexplored. Here, we found ASNS to be expressed in pericentral hepatocytes, a population of hepatic cells specialized in xenobiotic detoxification. ASNS expression was strongly enhanced in 2 models of acute liver injury: carbon tetrachloride (CCl4) and acetaminophen. We found that mice with hepatocyte-specific Asns deletion were more prone to pericentral liver damage than their control littermates after toxin exposure. This phenotype could be reverted by i.v. administration of asparagine. Unexpectedly, the stress-induced upregulation of ASNS involved an ATF4-independent, noncanonical pathway mediated by the nuclear receptor, liver receptor homolog 1 (LRH-1; NR5A2). Altogether, our data indicate that the induction of the asparagine-producing enzyme ASNS acts as an adaptive mechanism to constrain the necrotic wave that follows toxin administration and provide proof of concept that i.v. delivery of asparagine can dampen hepatotoxin-induced pericentral hepatocellular death.
MYC-mediated resistance to trametinib and HCQ in PDAC is overcome by CDK4/6 and lysosomal inhibition
Authors: Mark R. Silvis, Dilru Silva, Riley Rohweder, Sophia Schuman, Swapna Gudipaty, Amanda Truong, Jeffrey Yap, Kajsa Affolter, Martin McMahon, Conan Kinsey
Journal: The Journal of Experimental Medicine (2023)

Pharmacological inhibition of KRAS>RAF>MEK1/2>ERK1/2 signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDAC). Interestingly, combined inhibition of MEK1/2 (with trametinib [T]) plus autophagy (with chloroquine [CQ] or hydroxychloroquine [HCQ]) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDAC cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ-resistant PDAC tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of P/HCQ.
Outcome of COVID-19 in hospitalised immunocompromised patients: An analysis of the WHO ISARIC CCP-UK prospective cohort study
Authors: Lance Turtle, Mathew Thorpe, Thomas M. Drake, Maaike Swets, Carlo Palmieri, Clark D. Russell, Antonia Ho, Stephen Aston, Daniel G. Wootton, Alex Richter, Thushan I. de Silva, Hayley E. Hardwick, Gary Leeming, Andy Law, Peter J. M. Openshaw, Ewen M. Harrison, J. Kenneth Baillie, Malcolm G. Semple, Annemarie B. Docherty
Journal: PLoS Medicine (2023)

Background Immunocompromised patients may be at higher risk of mortality if hospitalised with Coronavirus Disease 2019 (COVID-19) compared with immunocompetent patients. However, previous studies have been contradictory. We aimed to determine whether immunocompromised patients were at greater risk of in-hospital death and how this risk changed over the pandemic. Methods and findings We included patients &gt; = 19 years with symptomatic community-acquired COVID-19 recruited to the ISARIC WHO Clinical Characterisation Protocol UK prospective cohort study. We defined immunocompromise as immunosuppressant medication preadmission, cancer treatment, organ transplant, HIV, or congenital immunodeficiency. We used logistic regression to compare the risk of death in both groups, adjusting for age, sex, deprivation, ethnicity, vaccination, and comorbidities. We used Bayesian logistic regression to explore mortality over time. Between 17 January 2020 and 28 February 2022, we recruited 156,552 eligible patients, of whom 21,954 (14%) were immunocompromised. In total, 29% ( n = 6,499) of immunocompromised and 21% ( n = 28,608) of immunocompetent patients died in hospital. The odds of in-hospital mortality were elevated for immunocompromised patients (adjusted OR 1.44, 95% CI [1.39, 1.50], p &lt; 0.001). Not all immunocompromising conditions had the same risk, for example, patients on active cancer treatment were less likely to have their care escalated to intensive care (adjusted OR 0.77, 95% CI [0.7, 0.85], p &lt; 0.001) or ventilation (adjusted OR 0.65, 95% CI [0.56, 0.76], p &lt; 0.001). However, cancer patients were more likely to die (adjusted OR 2.0, 95% CI [1.87, 2.15], p &lt; 0.001). Analyses were adjusted for age, sex, socioeconomic deprivation, comorbidities, and vaccination status. As the pandemic progressed, in-hospital mortality reduced more slowly for immunocompromised patients than for immunocompetent patients. This was particularly evident with increasing age: the probability of the reduction in hospital mortality being less for immunocompromised patients aged 50 to 69 years was 88% for men and 83% for women, and for those &gt;80 years was 99% for men and 98% for women. The study is limited by a lack of detailed drug data prior to admission, including steroid doses, meaning that we may have incorrectly categorised some immunocompromised patients as immunocompetent. Conclusions Immunocompromised patients remain at elevated risk of death from COVID-19. Targeted measures such as additional vaccine doses, monoclonal antibodies, and nonpharmaceutical preventive interventions should be continually encouraged for this patient group. Trial registration ISRCTN 66726260 .
Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice
Authors: Hao-Yu Zou, Lin Guo, Bei Zhang, Si Chen, Xin-Rong Wu, Xian-Dong Liu, Xin-Yu Xu, Bin-Yin Li, Shengdi Chen, Nan-Jie Xu, Suya Sun
Journal: Journal of Clinical Investigation (2023)
Utility of new image-derived biomarkers for autosomal dominant polycystic kidney disease prognosis using automated instance cyst segmentation
Authors: Adriana V. Gregory, Fouad T. Chebib, Bhavya Poudyal, Heather L. Holmes, Alan S.L. Yu, Douglas P. Landsittel, Kyongtae T. Bae, Arlene B. Chapman, Rahbari-Oskoui Frederic, Michal Mrug, William M. Bennett, Peter C. Harris, Bradley J. Erickson, Vicente E. Torres, Timothy L. Kline
Journal: Kidney International (2023)

New image-derived biomarkers for patients affected by autosomal dominant polycystic kidney disease are needed to improve current clinical management. The measurement of total kidney volume (TKV) provides critical information for clinicians to drive care decisions. However, patients with similar TKV may present with very different phenotypes, often requiring subjective decisions based on other factors (e.g., appearance of healthy kidney parenchyma, a few cysts contributing significantly to overall TKV, etc.). In this study, we describe a new technique to individually segment cysts and quantify biometric parameters including cyst volume, cyst number, parenchyma volume, and cyst parenchyma surface area. Using data from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study the utility of these new parameters was explored, both quantitatively as well as visually. Total cyst number and cyst parenchyma surface area showed superior prediction of the slope of estimated glomerular filtration rate decline, kidney failure and chronic kidney disease stages 3A, 3B, and 4, compared to TKV. In addition, presentations such as a few large cysts contributing significantly to overall kidney volume were shown to be much better stratified in terms of outcome predictions. Thus, these new image biomarkers, which can be obtained automatically, will have great utility in future studies and clinical care for patients affected by autosomal dominant polycystic kidney disease.
Multiplex immune profiling reveals the role of serum immune proteomics in predicting response to preoperative chemotherapy of gastric cancer
Authors: Zhaoqing Tang, Yuan Gu, Zhongyi Shi, Lingqiang Min, Ziwei Zhang, Peng Zhou, Rongkui Luo, Yan Wang, Yuehong Cui, Yihong Sun, Xuefei Wang
Journal: Cell Reports Medicine (2023)

Responses toward preoperative chemotherapy are heterogeneous in patients with gastric adenocarcinoma. Existing studies in the field focus heavily on the tumor microenvironment (TME), whereas little is known about the relationship between systemic immunity and chemotherapy response. In this study, we collect serum samples from patients with gastric adenocarcinoma before, on, and after preoperative chemotherapy and study their immune proteomics using an antibody-based proteomics panel. We also collect surgically resected tumor samples and incorporate multiple methods to assess their TME. We find that both local and systemic immune features are associated with treatment response. Preoperative chemotherapy induces a sophisticated systemic immune response indicated by dynamic serum immune proteomics. A pretreatment serum protein scoring system is established for response prediction. Together, these findings highlight the fundamental but largely underestimated role of systemic immunity in the treatment of gastric cancer, suggesting a patient stratification strategy based on pretreatment serum immune proteomics.
Antimicrobial resistance in patients with COVID-19: a systematic review and meta-analysis
Authors: Bradley J Langford, Miranda So, Marina Simeonova, Valerie Leung, Jennifer Lo, Tiffany Kan, Sumit Raybardhan, Mia E Sapin, Kwadwo Mponponsuo, Ashley Farrell, Elizabeth Leung, Jean-Paul R Soucy, Alessandro Cassini, Derek MacFadden, Nick Daneman, Silvia Bertagnolio
Journal: The Lancet Microbe (2023)

BackgroundFrequent use of antibiotics in patients with COVID-19 threatens to exacerbate antimicrobial resistance. We aimed to establish the prevalence and predictors of bacterial infections and antimicrobial resistance in patients with COVID-19.MethodsWe did a systematic review and meta-analysis of studies of bacterial co-infections (identified within ≤48 h of presentation) and secondary infections (>48 h after presentation) in outpatients or hospitalised patients with COVID-19. We searched the WHO COVID-19 Research Database to identify cohort studies, case series, case-control trials, and randomised controlled trials with populations of at least 50 patients published in any language between Jan 1, 2019, and Dec 1, 2021. Reviews, editorials, letters, pre-prints, and conference proceedings were excluded, as were studies in which bacterial infection was not microbiologically confirmed (or confirmed via nasopharyngeal swab only). We screened titles and abstracts of papers identified by our search, and then assessed the full text of potentially relevant articles. We reported the pooled prevalence of bacterial infections and antimicrobial resistance by doing a random-effects meta-analysis and meta-regression. Our primary outcomes were the prevalence of bacterial co-infection and secondary infection, and the prevalence of antibiotic-resistant pathogens among patients with laboratory-confirmed COVID-19 and bacterial infections. The study protocol was registered with PROSPERO (CRD42021297344).FindingsWe included 148 studies of 362 976 patients, which were done between December, 2019, and May, 2021. The prevalence of bacterial co-infection was 5·3% (95% CI 3·8–7·4), whereas the prevalence of secondary bacterial infection was 18·4% (14·0–23·7). 42 (28%) studies included comprehensive data for the prevalence of antimicrobial resistance among bacterial infections. Among people with bacterial infections, the proportion of infections that were resistant to antimicrobials was 60·8% (95% CI 38·6–79·3), and the proportion of isolates that were resistant was 37·5% (26·9–49·5). Heterogeneity in the reported prevalence of antimicrobial resistance in organisms was substantial (I2=95%).InterpretationAlthough infrequently assessed, antimicrobial resistance is highly prevalent in patients with COVID-19 and bacterial infections. Future research and surveillance assessing the effect of COVID-19 on antimicrobial resistance at the patient and population level are urgently needed.FundingWHO.
The Michigan Genomics Initiative: A biobank linking genotypes and electronic clinical records in Michigan Medicine patients
Authors: Matthew Zawistowski, Lars G. Fritsche, Anita Pandit, Brett Vanderwerff, Snehal Patil, Ellen M. Schmidt, Peter VandeHaar, Cristen J. Willer, Chad M. Brummett, Sachin Kheterpal, Xiang Zhou, Michael Boehnke, Gonçalo R. Abecasis, Sebastian Zöllner
Journal: Cell Genomics (2023)

Biobanks of linked clinical patient histories and biological samples are an efficient strategy to generate large cohorts for modern genetics research. Biobank recruitment varies by factors such as geographic catchment and sampling strategy, which affect biobank demographics and research utility. Here, we describe the Michigan Genomics Initiative (MGI), a single-health-system biobank currently consisting of >91,000 participants recruited primarily during surgical encounters at Michigan Medicine. The surgical enrollment results in a biobank enriched for many diseases and ideally suited for a disease genetics cohort. Compared with the much larger population-based UK Biobank, MGI has higher prevalence for nearly all diagnosis-code-based phenotypes and larger absolute case counts for many phenotypes. Genome-wide association study (GWAS) results replicate known findings, thereby validating the genetic and clinical data. Our results illustrate that opportunistic biobank sampling within single health systems provides a unique and complementary resource for exploring the genetics of complex diseases.
Reactive gene curation to support interpretation and reporting of a clinical genome test for rare disease: Experience from over 1,000 cases
Authors: Amanda R. Clause, Julie P. Taylor, Revathi Rajkumar, Krista Bluske, Maren Bennett, Laura M. Amendola, David R. Bentley, Ryan J. Taft, Denise L. Perry, Alison J. Coffey, Carolyn Brown, Matthew P. Brown, Amanda Buchanan, Brendan Burns, Nicole J. Burns, Anjana Chandrasekhar, Aditi Chawla, Katie Golden-Grant, Akanchha Kesari, Alka Malhotra, Becky Milewski, Samin A. Sajan, Zinayida Schlachetzki, Sarah Schmidt, Brittany Thomas, Erin Thorpe
Journal: Cell Genomics (2023)

Current standards in clinical genetics recognize the need to establish the validity of gene-disease relationships as a first step in the interpretation of sequence variants. We describe our experience incorporating the ClinGen Gene-Disease Clinical Validity framework in our interpretation and reporting workflow for a clinical genome sequencing (cGS) test for individuals with rare and undiagnosed genetic diseases. This “reactive” gene curation is completed upon identification of candidate variants during active case analysis and within the test turn-around time by focusing on the most impactful evidence and taking advantage of the broad applicability of the framework to cover a wide range of disease areas. We demonstrate that reactive gene curation can be successfully implemented in support of cGS in a clinical laboratory environment, enabling robust clinical decision making and allowing all variants to be fully and appropriately considered and their clinical significance confidently interpreted.
Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial
Authors: Reinier C A van Linschoten, Fenna M Jansen, Renske W M Pauwels, Lisa J T Smits, Femke Atsma, Wietske Kievit, Dirk J de Jong, Annemarie C de Vries, Paul J Boekema, Rachel L West, Alexander G L Bodelier, Ingrid A M Gisbertz, Frank H J Wolfhagen, Tessa E H Römkens, Maurice W M D Lutgens, Adriaan A van Bodegraven, Bas Oldenburg, Marieke J Pierik, Maurice G V M Russel, Nanne K de Boer, Rosalie C Mallant-Hent, Pieter C J ter Borg, Andrea E van der Meulen-de Jong, Jeroen M Jansen, Sita V Jansen, Adrianus C I T L Tan, C Janneke van der Woude, Frank Hoentjen, Desirée van Noord, Jildou Hoekstra, Johannes T. Kamphuis, Moniek H.P. Gorter, Aura A.J. van Esch
Journal: The Lancet. Gastroenterology & hepatology (2023)
Engineered high-strength biohydrogel as a multifunctional platform to deliver nucleic acid for ameliorating intervertebral disc degeneration
Authors: Tao Chen, Qiuping Qian, Pooyan Makvandi, Ehsan Nazarzadeh Zare, Qizhu Chen, Linjie Chen, Zhiguang Zhang, Hao Zhou, Wenxian Zhou, Hui Wang, Xiangyang Wang, Yu Chen, Yunlong Zhou, Aimin Wu
Journal: Bioactive Materials (2023)

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain. The strategy of using functional materials to deliver nucleic acids provides a powerful tool for ameliorating IVDD. However, the immunogenicity of nucleic acid vectors and the poor mechanical properties of functional materials greatly limit their effects. Herein, antagomir-204-3p (AM) shows low immunogenicity and effectively inhibits the apoptosis of nucleus pulposus cells. Moreover, a high-strength biohydrogel based on zinc-oxidized sodium alginate-gelatin (ZOG) is designed as a multifunctional nucleic acid delivery platform. ZOG loaded with AM (ZOGA) exhibits great hygroscopicity, antibacterial activity, biocompatibility, and biodegradability. Moreover, ZOGA can be cross-linked with nucleus pulposus tissue to form a high-strength collagen network that improves the mechanical properties of the intervertebral disc (IVD). In addition, ZOGA provides an advantageous microenvironment for genetic expression in which AM can play an efficient role in maintaining the metabolic balance of the extracellular matrix. The results of the radiological and histological analyses demonstrate that ZOGA restores the height of the IVD, retains moisture in the IVD, and maintains the tissue structure. The ZOGA platform shows the sustained release of nucleic acids and has the potential for application to ameliorate IVDD, opening a path for future studies related to IVD.
Outcomes of meningococcal serogroup B disease in children after implementation of routine infant 4CMenB vaccination in England: an active, prospective, national surveillance study
Authors: Anna A Mensah, Helen Campbell, Stephen A Clark, Sonia Ribeiro, Jay Lucidarme, Xilian Bai, Ray Borrow, Shamez N Ladhani
Journal: The Lancet Child & Adolescent Health (2023)